The extra-islet pancreas supports autoimmunity in human type 1 diabetes
2025
Graham L Barlow | Christian M Schürch | Salil S Bhate | Darci J Phillips | Arabella Young | Shen Dong | Hunter A Martinez | Gernot Kaber | Nadine Nagy | Sasvath Ramachandran | Janet Meng | Eva Korpos | Jeffrey A Bluestone | Garry P Nolan | Paul L Bollyky
In autoimmune type 1 diabetes (T1D), immune cells infiltrate and destroy the islets of Langerhans — islands of endocrine tissue dispersed throughout the pancreas. However, the contribution of cellular programs outside islets to insulitis is unclear. Here, using CO-Detection by indEXing (CODEX) tissue imaging and cadaveric pancreas samples, we simultaneously examine islet and extra-islet inflammation in human T1D. We identify four sub-states of inflamed islets characterized by the activation profiles of CD8+T cells enriched in islets relative to the surrounding tissue. We further find that the extra-islet space of lobules with extensive islet-infiltration differs from the extra-islet space of less infiltrated areas within the same tissue section. Finally, we identify lymphoid structures away from islets enriched in CD45RA+ T cells — a population also enriched in one of the inflamed islet sub-states. Together, these data help define the coordination between islets and the extra-islet pancreas in the pathogenesis of human T1D.
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